ARU-1801 Gene Therapy for Sickle Cell Associated with Improved Clinical Outcomes

Michael Grimley, MD

New data presented at the American Society of Gene & Cell Therapy (ASGCT) Virtual Meeting demonstrate the potential of ARU-1801 gene therapy for sickle cell disease (SCD).

A team led by Michael Grimley, MD, of Cincinnati Children’s Hospital Medical Center, reported on findings from the ongoing Phase 1/2 MOMENTUM study, which is evaluating the safety and efficacy of the new investigative gene therapy product among a sickle cell population. ARU-1801 consists of autologous CD34+ hematopoietic stem and progenitors (HSPCs) transduced with a lentiviral vector (LV) encoding a modified γ-globin^G16D gene.

“Preliminary studies in SCD mice have suggested HbF^G16D may have a more potent anti-sickling effect than wild-type HbF,” the team wrote. “As a high potency anti-sickling globin, HbF^G16D is believed to allow ARU-1801 to be effective with reduced intensity conditioning (RIC), resulting in fewer toxicities and lower resource utilization than myeloablative approaches, expanding access to gene therapy to a broader group of SCD patients.”

Thus, according to long-term clinical data, ARU-1801 demonstrated a favorable safety profile, and no treatment-related adverse events were reported. These were observed across 3 treated patients with >9 months of follow-up data.

The investigators noted that RIC led to neutrophil engraftment within 7-9 days (median, 7) of infusion and platelet engraftment within 6-12 days (median, 7).

Under the initial manufacturing, Patient 1 demonstrated a steady vector copy number of 0.2, in addition to stable expression of 20% HbF^G16D and 31% total anti-sickling globin (ASG). As noted by the investigators, ASG was composed of endogenous HbF, HbA2 and ARU-1801-derived HbF^G16D.

Further, the patients showed 64% F-cells 2 years following gene therapy infusion.

Grimley’s team indicated that Patient 2 had a sub-therapeutic exposure to melphalan secondary to renal hyperfiltration and rapid clearance of melphalan — as such, this resulted in engraftment (VCN, 0.1) and thus lower HBF^G16D.

Nevertheless, ASG expression was notably stable at 22%, as were F-cells at 36% 2 years post-infusion. This stability was due to sustained increases in endogenous HbF and HbA2.

Patient 3 had 10-month follow-up data (representative of the new manufacturing process) that showed a stable VCN of 0.7 with 41% ASG expression and 27% HbF^G16D at month 10. Additionally, the patient had 92% F-reticulocytes at month 6, which indicates near pan-cellular expression of HbF.

All 3 patients had a median of 21 vaso-occlusive episodes in the 24 months prior to treatment with ARU-1801. They were hospitalized for a median of 6 of those episodes.

However, through 24 months post-infusion, patient 1 had a 93% reduction in the number of vaso-occlusive episodes, and patient 2 had an 85% reduction in the number of episodes. Through 10-months of follow-up, patient 3 experienced 0 vaso-occlusive episodes, thus demonstrating a 100% reduction.

Even more, the cumulative days spent in hospital from these episodes decreased from a median of 15 to a median of 0 days, showing an average of a 93.8% reduction.

“Treatment with ARU-1801 has resulted in remarkable improvement in clinical outcomes,” Grimely and team wrote.

“These results are an encouraging sign of the therapeutic benefit of ARU-1801 with RIC for patients with SCD,” they concluded.

The study, “Early Results from a Phase 1/2 Study of ARU-1801 Gene Therapy for Sickle Cell Disease (SCD): Safety and Efficacy of a Modified Gamma Globin Lentivirus Vector and Reduced Intensity Conditioning Transplant,” was presented at ASGCT 2021.